The developing central nervous system is particularly vulnerable to environmental toxicants. While lead poisoning has been extensively studied and public health measures to reduce exposure implemented, exposure is still high in some populations. Other toxic metals (arsenic and manganese for example) remain elevated in the environment, and the effects of arsenic and manganese on neurodevelopment remain poorly understood. Critical questions also remain regarding individual differences in susceptibility to metals (even lead) and whether combinations of neurotoxicants are synergistically toxic. Given this, the effect of joint exposure to combinations of metals is a critical public health issue, as this exposure scenario is more reflective of the real world situation. The role of iron metabolism genes, which may regulate the metabolism of multiple neurotoxic metals, may also play a key role in understanding the mechanisms by which metal mixtures produce neurotoxicity. In this project we will establish a new birth cohort in Mexico City to measure biomarkers of internal dose for manganese, arsenic and lead and analyze their interactions in predicting associations between metal exposure and neurodevelopment. Furthermore, we will study the modifying effects of iron metabolism gene variants (HFE, Transferrin, Transferrin Receptor, and Divalent Metal Transport Protein-1) on the neurotoxicity of these metals and their influence on placenta! transfer of metals. We will also explore the effect of variants in the GST-M1, T1 and P1 genes on Arsenic neurotoxicity. Our research team is particularly well situated to conduct this work as we have a long-standing collaboration with the National Institute of Public Health in Mexico, enabling us to quickly assemble highly skilled field teams for sample collection and phenotyping. Furthermore, our pilot data suggest that exposure to Mn, As and Pb are elevated in the target population, and that biomarkers of internal dose may be associated with poorer developmental outcomes. [unreadable] [unreadable] [unreadable]